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Managing PCOS in General Practice. John Eden UNSW, RHW. Conflict of interest statement. In the last 10 years, I have been a paid scientific adviser for
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Managing PCOS in General Practice John Eden UNSW, RHW
Conflict of interest statement • In the last 10 years, I have been a paid scientific adviser for • Solvay Pharmaceuticals, Wyeth-Ayerst, Organon P/L, Novartis P/L, Novo-Nordisk, Arkopharma P/L, Roche Pharmaceuticals Lawley Pharmaceuticals, CSL, and AstraZenica P/L. • My research unit performs trials for the pharma, food & supplement industries
WHRIA and Country gynaecology services • What is WHRIA? • Clinical services • Information services (with UNSW). Example - PCOS awareness campaign. • Research (Barbara Gross Research Unit at RHW) • Country outreach clinics (with RDN) • Bourke, Moree • GPs – Other areas that need gynae services • Specialists who want to help • Contact me at info@WHRIA.com.au
Definition of hirsutism • Excessive terminal hair (black & coarse) that appears in a male pattern in women • Patient and doctor attitudes towards hirsutism can be quite different • Affects up to 15% of women • Obviously there are racial differences
Is Hirsutism hormonal? • Most hirsute women have PCO (90%, Adams, 1986) & the severity correlates some-what with serum androgens & 5a-reductase activity • Most women with acne have PCO (Bunker, 1989; severity poorly correlates with androgens) • PCO is found in 26% with amenorrhoea & 87% with oligomenorrhoea (Adams, 1986; severity correlates with serum androgens)
Differential Diagnosis • PCOS – the vast majority • Other medical causes • Cushing’s syndrome • Adrenal, ovarian tumours • Self-medication (testosterone, anabolic steroids) • Idiopathic
Polycystic ovaries A Morphologic diagnosis • ‘Presence of 12 or more follicles in each • ovary measuring 2-9mm in diameter &/or increased ovarian volume (>10ml)’ One in four women have PCO on scan
PCO syndrome definition Revised 2003 Rotterdam ESHRE/ASRM (2 out of 3) – • Irregular periods • Evidence of raised male hormone levels • PCO & exclusion of other causes
Genetic Intra-uterine Nutritional Hormonal Fat Insulin Skin sensitivity Disordered ovulation Hirsutism, acne
Probably all women with hirsutism should have some tests • LH, FSH, TSH, PRL, Total T, SHBG, DHEAS, 17OHP. • Fasting lipids, glucose. Maybe GTT (& insulins) • Scan – doesn’t add a lot • PCOS: Usually at least one of LH, T or SHBG is abnormal
Red Flags • Always repeat a grossly abnormal result • Congenital Adrenal Hyperplasia: markedly raised 17OHP (do Synacthen test) • Very high T (>6nmol/l) or DHEAS (twice the upper limit of normal): think tumour • Abnormal GTT • Raised triglycerides (may be a sign of severe IR)
Insulin Resistance IR occurs in 30-60% of women with PCOS (Dunaif, 1992) IR is a post-receptor phenomenon, multifactorial & is mostly sited in the fat, muscle & liver, but the ovaries remain spared. Raised serum insulin levels stimulate ovarian androgen production & decrease hepatic SHBG production. IR is associated with adverse CVS surrogates (raised lipids, especially triglycerides & hypertension) Insulin sensitizers (metformin, the glizones) improve the androgenic profile & may induce ovulation.
Hair removal • Waxes, creams • Shaving • Electrolysis • Laser
Insulin Resistance • Low GI diet • Exercise • Metformin • Other weight loss strategies • Weight loss drinks • Drugs • Weight loss surgery
Metformin • Safe when used to treat gestational diabetes (MiG trial, N= 751, N Engl J Med 2008; 358: 2003-15) • Not associated with increased fetal abnormalities when used in first trimester (meta-analysis, 172 treated, 235 controls, Fert Ster Vol. 86, No. 3, September 2006) • Helps restore the cycle, & lowers risk of diabetes but doesn’t help hirsutism much
Statins • Many women with PCOS have adverse CVS markers which can be reversed with a statin • Statins inhibit proliferation and steroidogenesis of ovarian theca–interstitial cells in culture • Pawelczyk recently presented data on 60 women with PCOS randomised to simvastatin 20mg or metformin 850mg bd or both (Society for Reproductive Endocrinology and Infertility meeting 2008)
Results • Note • These data are very preliminary • Statins have been linked to birth defects
Menstrual problems • delayed first period • infrequent periods • heavy bleeding • continual bleeding Contraception requirements
Tranexamic acid • Anti-fibrinolytic • Safe, sold over the counter in Europe. • Dosage: 1g 3-4 times a day, day 1-5 • Very effective for heavy periods – usually more than halves the flow. Superior to OCP. • Side effects: nausea with doses >6g/day
Contraceptive Pill • Takes months to help hirsutism. • Effective for heavy periods. Can skip periods. Contraceptive. Superior to metformin for skin problems • Side effects: watch triglycerides & BP (oestrogen) & weight gain with CPA. Might aggravate IR. ‘PMT’ with progestin.
Progestins • Cyclical vs continuous • Uses: to stop a heavy period. Every 2m to prevent uterine lining build up • Side effects: ‘PMT’ (1/8); some have an adverse effect on IR. Dydrogesterone has no measurable metabolic effect.
Spironolactone • Need at least 100mg for anti-androgen effect • Used for skin problems, but often shortens the cycle. • Takes months to work • Side effects: diuretic
Eflornithine Cream • Eflornithine is an irreversible inhibitor of ornithine decarboxylase which in turn slows hair growth. Works in 2/3 in 4-8 weeks • Use sparingly. Tube lasts 3-4 months • Side effects: ‘tingling’
Clinical Trials • Two double-blind, randomised, parallel, vehicle-controlled studies performed with 596 women diagnosed with UFH were carried out • Subjects were randomised to receive Eflornithine or vehicle cream, applied topically twice daily for 24 weeks • By 8-weeks the active treatment had significantly better results than placebo. Eflornithine helped around 2/3 women
Clinical Trials • Side effects reported occurred at similar frequencies in Eflornithine and control groups, with most being skin-related. Side effects are primarily mild and resolve without medical treatment or discontinuation. It can sometimes aggravate acne. • Eflornithine has not been associated with phototoxic or photosensitisation reactions • A trial combining Eflornthine with laser hair removal, showed the women on active treatment needed fewer laser treatments
Levonorgestrel-IUD • Mechanism of action: progestin containing IUD. Safe, cheap, lasts 5 years. Very effective for heavy periods. • Contraceptive, reversible. • Side effects: Might need a GA to get it in. • Spotting for up to 3m. Can fall out. Risk of PID is ½ normal because of progestin’s effect on cervical mucus. Very little systemic effect.
Take Home Messages • PCO is common (1 in 4) & women with PCO & >6 periods a year are normal. • PCOS = PCO and symptoms • Around ½ women with PCOS & irregular periods, have IR • Measure lipids & fasting glucose in everyone (even the young) • For women with PCOS think about doing a 75g GTT (insulin & glucose levels)
Take Home Messages • Dietary recommendations: low GI, low fat diet • OCP – may increase triglyceride levels, but OCP better than metformin for acne & hirsutism. • Anti-androgens & Eflornithine lotion for hirsutism or acne • Metformin may be useful to help IR, aids weight loss & may induce ovulation. Doesn’t help hirsutism much. • Consider weight loss surgery for severely obese patients
Take Home Messages • Tranexamic acid will control heavy periods if the uterus is normal. • The Levonorgestrel-IUD is an excellent option for many women with PCOS as it controls heavy periods & prevents uterine cancer; without metabolic effects. It is cheap, lasts 5 years and on removal, fertility returns immediately.
Ms TG, 14y young woman with irregular heavy periods with flooding. She has about 3-4 periods a year. Tests show she has PCOS, but no evidence of metabolic syndrome. She is anaemic with low iron studies. Ultrasound scan shows an 8cm normal uterus
Tranexamic acid Progestins OCP Metformin
A 25y woman having 1-2 periods per year. BP 150/90; BMI 32. General exam nad, except acanthosis both axillae. Cholesterol 6; TG 4.5 Fasting glucose 5.8 Fasting insulin 50u/l
Treat IR Tranexamic acid Cyclical dydrogesterone Levonorgestrel-IUD OCP
28 year old with PCOS & heavy periods. She also has acne & excess hair. Normal BP and no evidence of metabolic syndrome
OCP (& spironolactone) Eflornithine cream Hair removal Levonorgestrel-IUD Tranexamic acid Progestins
28 year old woman with 12m infertility. She has 6 periods a year. Tests confirm PCOS. BMI 31.
Check other fertility factors Weight loss Metformin or clomiphene Monitor ovulation when cycles regular (BBT charts, LH kits)
58 year old post-menopausal woman with excess facial hair. Most is light, ‘peach-fuzz,’ and some dark course terminal hair. She is not on HRT. Serum androgens normal.
Eflornithine cream Hair removal Spironolactone